Drugs for TB

Question 1

What is the percentage of individuals infected with M. tuberculosis that will have containment of the disease?

Answer 1

More than 90%

Question 2

Enumerate at least 4 challenges in treating Mycobacteria.

Answer 2

Any four of the following: Grow slowly, resistance to drugs, dormancy, lipid-rich cell wall, intracellular pathogens

Question 3

Why are antibiotics that are most active against rapidly growing cells relatively ineffective against Mycobacteria?

Answer 3

Mycobacteria grow slowly

Question 4

Why is the lipid-rich cell wall of Mycobacteria a challenge in treatment?

Answer 4

It is impermeable to many agents.

Question 5

What is the approximate number of drug-resistant mutants per Mycobacterium tuberculosis bacillus?

Answer 5

1 in 10^6

Question 6

What are the implications of the fact that some second-line drugs for TB are commonly used antibiotics for URTI and UTI?

Answer 6

Overuse of these antibiotics could lead to the development of resistance in M. tuberculosis.

Question 7

Why is the use of multiple drugs in combination more effective than single-drug therapy for TB?

Answer 7

The probability of a bacillus being resistant to multiple drugs is much lower than the probability of it being resistant to a single drug.

Question 8

What is the probability of a Mycobacterium tuberculosis bacillus being resistant to both isoniazid and rifampicin?

Answer 8

1 in 10^12

Question 9

For how long should isoniazid and rifampicin be administered to cure 95-98% of pulmonary TB caused by susceptible strains?

Answer 9

9 months

Question 10

What is the effect of adding pyrazinamide to isoniazid and rifampicin therapy for the first 2 months?

Answer 10

It shortens the treatment duration to 6 months.

Question 11

What is the effect of adding ethambutol to the standard isoniazid and rifampicin regimen?

Answer 11

It does not shorten treatment but increases coverage for resistance.

Question 12

Which TB subpopulation is targeted by streptomycin?

Answer 12

TB subpopulations inside cavities

Question 13

Why is pyrazinamide effective against TB subpopulations in closed lesions and inside macrophages?

Answer 13

PZA prefers an acidic milieu, which is found in closed lesions and macrophages.

Question 14

What is the drug of choice for treating TB?

Answer 14

Isoniazid

Question 15

Isoniazid is structurally similar to what vitamin?

Answer 15

Pyridoxine

Question 16

Against what type of M. tuberculosis bacilli is isoniazid bactericidal?

Answer 16

Actively/rapidly growing bacilli

Question 17

What enzyme activates isoniazid?

Answer 17

KatG (mycobacterial catalase-peroxidase)

Question 18

Mutations in which two genes are associated with isoniazid resistance?

Answer 18

InhA and KatG

Question 19

What enzyme is inhibited by activated isoniazid?

Answer 19

Enoyl-acyl carrier protein reductase (InhA)

Question 20

What advice is given to patients regarding food intake when taking isoniazid?

Answer 20

Take isoniazid at least 30 minutes before food.

Question 21

How is the metabolism of isoniazid genetically determined?

Answer 21

By the rate of acetylation by liver N-acetyl transferase. There are fast and slow acetylators.

Question 22

What is the typical daily dose of isoniazid?

Answer 22

5 mg/kg/day

Question 23

What supplement is recommended for patients taking isoniazid, and why?

Answer 23

Pyridoxine (25-50 mg/day), to prevent peripheral neuropathy due to relative pyridoxine deficiency

Question 24

What is the most severe side effect of isoniazid?

Answer 24

Hepatitis

Question 25

List three groups of individuals who are at increased risk of developing isoniazid-induced hepatitis.

Answer 25

Any three of the following: Elderly, alcoholic drinkers, pregnant and postpartum individuals, patients taking rifampicin

Question 26

What are the symptoms of isoniazid-induced hepatitis?

Answer 26

Loss of appetite, nausea, vomiting, jaundice, RUQ pain

Question 27

What percentage of patients develop isoniazid-induced hepatitis?

Answer 27

0.01

Question 28

What is the cause of isoniazid-induced peripheral neuropathy?

Answer 28

Relative pyridoxine (Vitamin B6) deficiency

Question 29

List five conditions that predispose patients to isoniazid-induced peripheral neuropathy.

Answer 29

Any five of the following: Slow acetylators, malnutrition, alcoholism, diabetes, AIDS, uremia

Question 30

How is isoniazid-induced peripheral neuropathy reversed?

Answer 30

By administration of pyridoxine (10 mg/day)

Question 31

What is the characteristic finding in urine, sweat, and tears of patients taking rifampicin?

Answer 31

Orange color

Question 32

What is the mechanism of action of rifampicin?

Answer 32

Binds to the β-subunit of bacterial DNA-dependent RNA polymerase and inhibits RNA synthesis.

Question 33

Mutations in which gene are responsible for rifampicin resistance?

Answer 33

rpoB

Question 34

What type of cells does rifampicin readily penetrate?

Answer 34

Most tissues and phagocytic cells

Question 35

What is the half-life of rifampicin?

Answer 35

3.5 hours

Question 36

What is the effect of rifampicin on cytochrome P450 enzymes?

Answer 36

Potent inducer

Question 37

What is the recommended daily dose of rifampicin?

Answer 37

10 mg/kg/day

Question 38

What type of mycobacterial infections is rifampicin effective against?

Answer 38

Atypical mycobacterial infections

Question 39

What effect does rifampicin have on serum levels of other drugs?

Answer 39

Lowers serum levels

Question 40

Why is it necessary to adjust the dose of other medications when they are used concurrently with rifampicin?

Answer 40

Rifampicin induces cytochrome P450, which increases the metabolism and clearance of other drugs.

Question 41

What is pyrazinamide a relative of?

Answer 41

Nicotinamide

Question 42

At what pH is pyrazinamide most active?

Answer 42

Acidic pH 5.5

Question 43

What enzyme converts pyrazinamide to its active form?

Answer 43

Pyrazinamidase (PncA)

Question 44

What is the active form of pyrazinamide?

Answer 44

Pyrazinoic acid

Question 45

What enzyme is inhibited by the active form of pyrazinamide?

Answer 45

Fatty acid synthetase I (FAT I)

Question 46

What is the half-life of pyrazinamide?

Answer 46

8-11 hours

Question 47

What is the recommended daily dose of pyrazinamide?

Answer 47

25 mg/kg/day

Question 48

What is the role of pyrazinamide in shortening the duration of TB therapy?

Answer 48

It is a sterilizing agent used during the first 2 months of therapy that targets residual intracellular organisms.

Question 49

What is the most common adverse reaction associated with pyrazinamide?

Answer 49

Hepatotoxicity

Question 50

What other adverse reactions are associated with pyrazinamide?

Answer 50

Nausea, vomiting, drug fever, hyperuricemia

Question 51

Is hyperuricemia a reason to stop pyrazinamide treatment?

Answer 51

No, it is not usually a reason to halt treatment.

Question 52

What is the mechanism of action of ethambutol?

Answer 52

Inhibits mycobacterial arabinosyl transferases

Question 53

What operon encodes the arabinosyl transferases inhibited by ethambutol?

Answer 53

embCAB operon

Question 54

What is the bactericidal or bacteriostatic nature of ethambutol?

Answer 54

Bacteriostatic

Question 55

What is the half-life of ethambutol?

Answer 55

4 hours

Question 56

What is the recommended daily dose of ethambutol?

Answer 56

15-25 mg/kg/day

Question 57

What is the most common serious adverse reaction associated with ethambutol?

Answer 57

Retrobulbar neuritis

Question 58

What visual disturbances are associated with ethambutol-induced retrobulbar neuritis?

Answer 58

Loss of visual acuity and red-green color blindness

Question 59

In what population is ethambutol relatively contraindicated?

Answer 59

Very young children

Question 60

Streptomycin interferes with the translation of mRNA transcripts in *M. tuberculosis* by binding to what ribosomal protein?

Answer 60

S12